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Several promising therapies for newly diagnosed and relapsed diffuse large B-cell lymphoma (DLBCL) patients have been recently approved or are in the final stages of development, including enhanced monoclonal antibodies, antibody-drug conjugates, and T-cell–engaging therapies.

Over the last few years, the bottom-line approach to DLBCL, the most common B-cell lymphoma, has changed tremendously, as described in a recent review in the .

In the following interview, the paper's co-author (with Nancy Bartlett, MD), Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center in Houston, where she is deputy chair, director of the Lymphoma Outcomes Database, and section chief of New Drug Development in the Department of Lymphoma/Myeloma, discusses the rapidly evolving treatment landscape in DLBCL and potential changes in practice.

What are some of the major advances the review mentions?

Nastoupil: The review highlights transformative major changes in first-line, second-line, and later lines of therapy. In first-line, we have exchanged vincristine with polatuzumab vedotin, with front-line, phase III trials showing positive results. The second-line incorporates CD19-directed CAR T-cell therapy with autologous transplant for those patients who relapse within 1 year. Both axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) have shown positive results in phase III studies.

In the third-line or later, we use CAR T-cell therapy with tisagenlecleucel (tisa-cel), or one of several other targeted agents, such as CD19-targeted loncastuximab, an antibody-drug conjugate, or tafasitamab, a naked CD19 antibody, combined with lenalidomide. Now the question is how to sequence and select the appropriate therapy.

How will the introduction of polatuzumab vedotin change front-line treatment?

Nastoupil: We need to expand our options in first-line therapy. If we improve results in the first-line, we won't have to deal with later lines of therapy. Randomized phase III studies show a 6% improvement in progression-free survival (PFS) and no difference in overall survival (OS) with polatuzumab vedotin. Even so, these were positive, statistically significant differences, with a 27% reduction in the risk of progression or death.

Cost may be an issue with polatuzumab vedotin. Cost-effectiveness studies show an advantage to using polatuzumab, but in clinical practice we will have to wait and see. It may take a few years for the landscape to evolve.

What is the advantage of using CAR T cell therapies as second-line or later therapy?

Nastoupil: CAR T-cell therapy is a major shift in the treatment approach. Since the mid- to late-1990s, we have been able to cure 60% of patients with chemotherapy-sensitive disease with platinum-based salvage therapy and autologous transplant. For those who progress within 12 months, rituximab cures only 20% of these patients. There is a debate whether to move forward to transplant if a patient does not attain a complete remission (CR) on PET.

CAR T-cell therapy works well in the third-line setting. It has dramatically improved survival to 12 to 25 months from the historical data of 6 months without cellular therapy, which is a significant change. This led to moving CAR T-cell therapy to earlier lines for patients who are less likely to relapse within 12 months.

In three large studies testing CAR T-cell therapy against standard therapy, axi-cel and liso-cel clearly led to better PFS and disease-free survival, and a trend toward OS. In the third study, tisa-cel was not as effective. However, the tisa-cel arm included more high-risk patients and those with primary refractory lymphoma, and patients received two cycles of chemotherapy while they were waiting for CAR T cell manufacture.

We have two CAR T-cell therapies that are better than standard therapy and more favorable for efficacy, so it's a no-brainer to move to second-line therapy for patients who have relapsed.

CAR T-cell therapy has its issues. It requires a specialized center to conduct leukapheresis, a wait time to manufacture the product, and the ability to manage potential late toxicities. It does not meet the great unmet need, but it is a critical component to therapy for early relapsed patients.

Which novel therapies on the horizon show the most promise?

Nastoupil: Bispecifics could address the challenges of CAR T-cell therapy. These off-the-shelf products created by the patient's own T cells mostly use CD20 antibodies, which have been proven an effective strategy with the use of rituximab. Clinical trial efficacy looks good, although we have no head-to-head comparisons of bispecifics with CAR T-cell therapy.

In phase II studies, for patients who have progressed post-CAR T-cell therapy, bispecifics achieve durable CR in 20-30% of patients. Bispecifics are well tolerated with step-up dosing and, with steroid premedication, they can be used safely.

The two most promising bispecifics are glofitamab and epcoritamab. FDA approval is expected this spring or later this year for DLBCL patients after two lines of systemic therapy.

How do you choose treatment for DLBCL patients?

Nastoupil: In my practice, for early relapse patients in the second-line setting, I choose CAR T-cell therapy. In the third-line setting, it depends on whether the patient has already received CAR T-cell therapy or not, and whether the disease is growing quickly. If the patient has not received CAR T-cell therapy I might prefer a bispecific first; post-CAR T-cell therapy, I choose the bispecific loncastuximab.

What is your bottom-line message for practicing oncologists?

Nastoupil: We have many good options for large-cell lymphoma, including some new ones. Don't be afraid to reach out to a local expert for advice on how to use new treatments, deal with nuances in toxicity, and questions about sequencing to optimize therapy, particularly if the patient is going to CAR T-cell therapy and has a wait time until cell manufacture.

Read the study here.